Although there has been evidence for cross-talk between the immune and nervous systems for years, the idea that immune molecules have non-immune functions in the normal developing nervous system has only recently gained credence. This idea is based on observations that the primary mediators of the adaptive immune response, major histocompatibility complex class I (MHCI) molecules, are expressed in the brain where they mediate activity-dependent refinement of connections. MHCI molecules are also attractive candidates for molecular mediators of the effects of an abnormal or strong immune response on the developing brain, which has been implicated in the pathogenesis of several neurodevelopmental disorders, including autism and schizophrenia. The central goal of this proposal is to determine the function of MHCI during the initial establishment of cortical connections, a comparable developmental stage to the time of the immune challenge that may predispose humans toward neurodevelopmental disorders. Using immunocyto- and histochemistry, electron microscopy, cell and slice culture and transfection, a novel long-term imaging assay, and whole-cell patch-clamp recording, we will address the following Aims. (1) To determine the localization of MHCI molecules in vivo and in vitro during cortical development. (2) To test the hypothesis that MHCI molecules regulate the initial establishment and function of cortical connections in vivo and in vitro. (3) To determine whether MHCI molecules negatively regulate the establishment of cortical connections by inhibiting synapse formation, increasing synapse elimination, or both. (4) To test the hypothesis that MHCI molecules act through natural killer cell receptors to negatively regulate the establishment of cortical connections. Results from this proposal should reveal novel functions of MHCI in the typically developing brain, as well as potential mechanisms for how they might contribute to neurodevelopmental disorders.